Gene-based medicine involves directly delivering a therapeutic or prophylactic gene product encoded in a nucleic acid molecule. The normal cellular transcription and translation machinery is utilized to manufacture the gene product in situ, where it is needed. When designed to integrate into the patient's genetic complement, in principle, genetic defects are curable. Moreover, when used to deliver prophylactic agents, like antigens in a vaccine regimen, quantitatively and qualitatively superior immune responses are possible.
Heretofore, however, gene-based medicine has suffered from deficiencies in delivery systems. While synthetic systems (e.g., liposome-based) and so called “naked-DNA” systems are available, they are notoriously inefficient. Thus, the delivery vehicles of choice are modified viruses. These too suffer from deficiencies, however. These deficiencies include limiting immune responses and manufacturing problems associated with obtaining infective virus.
Biolistic systems also are available. These typically entail coating metal beads with nucleic acids and delivering them with a “gene gun.” The gene gun physically shoots the DNA into whatever cells can be brought into its sights. The biolistic approach, however, is non-specific. It, thus, is sub-optimal in therapeutic and prophylactic methods where specific delivery is sought. For instance, in cancer treatment methods, it is desirable to deliver the gene product only to the cancer cell, or to immediately surrounding cells.
For vaccine applications, the product desirably is specifically delivered to the best antigen presenting cells. Conventional delivery, however, is insufficient in this regard. In fact, it is believed that most of the antigen presentation in current genetic vaccine methods is accomplished via muscle cells which can present antigen, but are far less efficient than the so-called “professional” antigen presenting cells of the monocyte lineage.
Monocytic cells play a central role in the immune response. They mature into the major antigen presenting cells of the body, macrophages and dendritic cells. Moreover, as tumors grow, as part of the angiogenic process, they produce macrophage attracting factor (MAF), which draws monocytic cells to the tumor. Thus, monocytic cells, if specifically targeted, could be used either to deliver therapeutic gene products to tumor cells or to generate a therapeutic or prophylactic immune response via their superior antigen presenting properties.
Monocytic cells normally patrol the body in search of foreign, non-self antigens, typically bacteria. The monocytic cells phagocytize the bacteria, which are then digested to smaller antigenic portions in the lysosome. The resultant bacterial antigens are cycled back to the surface for presentation to the humoral and cellular arms of the immune system.
Accordingly, there is a need in the art for more specific delivery systems for gene-based drugs. A suitable delivery system would have greater specificity than biolistic methods, be more efficient than existing synthetic systems, and be less sensitive to inactivation than viral-based delivery systems.